RESUMEN
IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (TH2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of TH2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.
Asunto(s)
Alérgenos , Hipersensibilidad a los Alimentos , Inmunoglobulina E , Humanos , Hipersensibilidad a los Alimentos/terapia , Hipersensibilidad a los Alimentos/inmunología , Animales , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Alérgenos/inmunología , Desensibilización Inmunológica/métodos , Células Th2/inmunología , Tolerancia Inmunológica , Susceptibilidad a EnfermedadesRESUMEN
The evolution of IgE in mammals added an extra layer of immune protection at body surfaces to provide a rapid and local response against antigens from the environment. The IgE immune response employs potent expulsive and inflammatory forces against local antigen provocation, at the risk of damaging host tissues and causing allergic disease. Two well-known IgE receptors, the high-affinity FcεRI and low-affinity CD23, mediate the activities of IgE. Unlike other known antibody receptors, CD23 also regulates IgE expression, maintaining IgE homeostasis. This mechanism evolved by adapting the function of the complement receptor CD21. Recent insights into the dynamic character of IgE structure, its resultant capacity for allosteric modulation, and the potential for ligand-induced dissociation have revealed previously unappreciated mechanisms for regulation of IgE and IgE complexes. We describe recent research, highlighting structural studies of the IgE network of proteins to analyze the uniquely versatile activities of IgE and anti-IgE biologics.
Asunto(s)
Productos Biológicos , Receptores de IgE , Humanos , Animales , Receptores de IgE/química , Receptores de IgE/metabolismo , Inmunoglobulina E/metabolismo , Receptores Fc , Mamíferos/metabolismoRESUMEN
The inflammasome components NLRP3 and ASC are cytosolic proteins, which upon sensing endotoxins or danger cues, form multimeric complexes to process interleukin (IL)-1ß for secretion. Here we found that antigen (Ag)-triggered degranulation of IgE-sensitized mast cells (MCs) was mediated by NLRP3 and ASC. IgE-Ag stimulated NEK7 and Pyk2 kinases in MCs to induce the deposition of NLRP3 and ASC on granules and form a distinct protein complex (granulosome) that chaperoned the granules to the cell surface. MCs deficient in NLRP3 or ASC did not form granulosomes, degranulated poorly in vitro and did not evoke systemic anaphylaxis in mice. IgE-Ag-triggered anaphylaxis was prevented by an NLRP3 inhibitor. In endotoxin-primed MCs, pro-IL-1ß was rapidly packaged into granules after IgE-Ag stimulation and processed within granule remnants by proteases after degranulation, causing lethal anaphylaxis in mice. During IgE-Ag-mediated degranulation of endotoxin-primed MCs, granulosomes promoted degranulation, combined with exteriorization and processing of IL-1ß, resulting in severe inflammation.
Asunto(s)
Anafilaxia , Inflamasomas , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Mastocitos , Anafilaxia/metabolismo , Inmunoglobulina E/metabolismo , Endotoxinas/metabolismo , Degranulación de la CélulaRESUMEN
In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the disease such as eosinophilia, mucus hypersecretion, bronchial hyperresponsiveness (BHR), IgE production, and susceptibility to exacerbations. However, only half the asthmatics have this "type 2-high" signature, and "type 2-low" asthma is more associated with obesity, presence of neutrophils, and unresponsiveness to corticosteroids, the mainstay asthma therapy. Here, we review the underlying immunological basis of various asthma endotypes by discussing results obtained from animal studies as well as results generated in clinical studies targeting specific immune pathways.
Asunto(s)
Asma/inmunología , Inmunidad Adaptativa , Células Epiteliales Alveolares/patología , Animales , Asma/fisiopatología , Asma/terapia , Asma/virología , Linfocitos B/inmunología , Terapia Biológica , Humanos , Inmunoglobulina E/inmunologíaRESUMEN
Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.
Asunto(s)
Basófilos/patología , Neuronas/patología , Prurito/patología , Enfermedad Aguda , Alérgenos/inmunología , Animales , Enfermedad Crónica , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Histamina/metabolismo , Humanos , Inmunoglobulina E/inmunología , Inflamación/patología , Leucotrienos/metabolismo , Mastocitos/inmunología , Ratones Endogámicos C57BL , Fenotipo , Prurito/inmunología , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
Asunto(s)
Linfocitos B/inmunología , Proteínas del Tejido Nervioso/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Autoanticuerpos/inmunología , Autoinmunidad , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas Ligadas a GPI/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Histonas/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismoRESUMEN
IgE-mediated allergy is a hypersensitivity disease affecting more than 25% of the population. The structures of the most common allergens have been revealed through molecular cloning technology in the past two decades. On the basis of this knowledge of the sequences and three-dimensional structures of culprit allergens, investigators can now analyze the immune recognition of allergens and the mechanisms of allergic inflammation in allergic patients. Allergy vaccines have been constructed that are able to selectively target the aberrant immune responses in allergic patients via different pathways of the immune system. Here we review various types of allergy vaccines that have been developed based on allergen structures, results from their clinical application in allergic patients, and future strategies for allergen-specific immunotherapy and allergy prophylaxis.
Asunto(s)
Alérgenos/genética , Alérgenos/inmunología , Hipersensibilidad/inmunología , Vacunas/inmunología , Alérgenos/química , Animales , Humanos , Hipersensibilidad/prevención & control , Hipersensibilidad/terapia , Inmunoglobulina E/inmunología , InmunoterapiaRESUMEN
The immune and nervous systems respond to dangerous stimuli to maintain homeostasis. In a recent issue of Nature, Florsheim et al. and Plum et al. uncover the crosstalk between immunoglobulin E (IgE)-mast-cell-mediated immune activation and neural responses driving behavioral avoidance of allergenic food.
Asunto(s)
Hipersensibilidad a los Alimentos , Mastocitos , Humanos , Presentación de Antígeno , Reacciones Cruzadas , Inmunoglobulina ERESUMEN
High-throughput 3' single-cell RNA-sequencing (scRNA-seq) allows cost-effective, detailed characterization of individual immune cells from tissues. Current techniques, however, are limited in their ability to elucidate essential immune cell features, including variable sequences of T cell antigen receptors (TCRs) that confer antigen specificity. Here, we present a strategy that enables simultaneous analysis of TCR sequences and corresponding full transcriptomes from 3'-barcoded scRNA-seq samples. This approach is compatible with common 3' scRNA-seq methods, and adaptable to processed samples post hoc. We applied the technique to identify transcriptional signatures associated with T cells sharing common TCRs from immunized mice and from patients with food allergy. We observed preferential phenotypes among subsets of expanded clonotypes, including type 2 helper CD4+ T cell (TH2) states associated with food allergy. These results demonstrate the utility of our method when studying diseases in which clonotype-driven responses are critical to understanding the underlying biology.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Hipersensibilidad al Cacahuete/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Células Th2/inmunología , Albuminas 2S de Plantas/inmunología , Animales , Antígenos de Plantas/inmunología , Células Cultivadas , Regiones Determinantes de Complementariedad/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunización , Inmunoglobulina E/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas E7 de Papillomavirus/inmunología , Análisis de la Célula Individual , Especificidad del Receptor de Antígeno de Linfocitos T/genética , TranscriptomaRESUMEN
Follicular regulatory T (TFR) cells have specialized roles in modulating follicular helper T (TFH) cell activation of B cells. However, the precise role of TFR cells in controlling antibody responses to foreign antigens and autoantigens in vivo is still unclear due to a lack of specific tools. A TFR cell-deleter mouse was developed that selectively deletes TFR cells, facilitating temporal studies. TFR cells were found to regulate early, but not late, germinal center (GC) responses to control antigen-specific antibody and B cell memory. Deletion of TFR cells also resulted in increased self-reactive immunoglobulin (Ig) G and IgE. The increased IgE levels led us to interrogate the role of TFR cells in house dust mite models. TFR cells were found to control TFH13 cell-induced IgE. In vivo, loss of TFR cells increased house-dust-mite-specific IgE and lung inflammation. Thus, TFR cells control IgG and IgE responses to vaccines, allergens and autoantigens, and exert critical immunoregulatory functions before GC formation.
Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Hipersensibilidad/inmunología , Neumonía/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Autoantígenos/inmunología , Supresión Clonal/genética , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Inmunidad Humoral , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Memoria Inmunológica , Interleucina-13/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pyroglyphidae/inmunologíaRESUMEN
IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.
Asunto(s)
Linfocitos B/fisiología , Carcinoma de Células Escamosas/inmunología , Células Epiteliales/fisiología , Inmunoglobulina E/metabolismo , Linfocitos Intraepiteliales/fisiología , Neoplasias Experimentales/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de IgE/metabolismo , Animales , Antracenos/toxicidad , Carcinoma de Células Escamosas/diagnóstico , Muerte Celular , Células Cultivadas , Regiones Determinantes de Complementariedad/genética , Daño del ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/genética , Vigilancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Experimentales/inducido químicamente , Piperidinas/toxicidad , Pronóstico , Receptores de Antígenos de Linfocitos T gamma-delta/genéticaRESUMEN
In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. To better understand IgE-BCR-mediated control of IgE responses, we developed whole-genome CRISPR screening that enabled comparison of IgE+ and IgG1+ B cell requirements for proliferation, survival, and differentiation into PCs. IgE+ PCs exhibited dependency on the PI3K-mTOR axis that increased protein amounts of the transcription factor IRF4. In contrast, loss of components of the calcium-calcineurin-NFAT pathway promoted IgE+ PC differentiation. Mice bearing a B cell-specific deletion of calcineurin B1 exhibited increased production of IgE+ PCs. Mechanistically, sustained elevation of intracellular calcium in IgE+ PCs downstream of the IgE-BCR promoted BCL2L11-dependent apoptosis. Thus, chronic calcium signaling downstream of the IgE-BCR controls the self-limiting character of IgE responses and may be relevant to the accumulation of IgE-producing cells in allergic disease.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Calcineurina/metabolismo , Hipersensibilidad/inmunología , Células Plasmáticas/inmunología , Animales , Apoptosis , Proteína 11 Similar a Bcl2/metabolismo , Calcineurina/genética , Señalización del Calcio , Diferenciación Celular , Supervivencia Celular , Células Cultivadas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Humanos , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Memoria Inmunológica , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
The contribution of the immunoglobulin E (IgE)-mast cell response to allergy portrays the axis as a villain with malicious intent. A new study from Starkl et al. tells a different story, highlighting a more worthwhile purpose of protecting us against bacterial toxins.
Asunto(s)
Hipersensibilidad , Inmunoglobulina E , Recuento de Células , Conciencia , Humanos , MastocitosRESUMEN
Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
Asunto(s)
Inmunidad Adaptativa/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Infecciones Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Alérgenos/inmunología , Animales , Femenino , Hipersensibilidad/inmunología , Hipersensibilidad/microbiología , Mastocitos/microbiología , Ratones , Ratones Endogámicos C57BL , Piel/inmunología , Piel/microbiología , Infecciones Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/microbiologíaRESUMEN
The steep rise in food allergy (FA) has evoked environmental factors involved in disease pathogenesis, including the gut microbiota, diet, and their metabolites. Early introduction of solid foods synchronizes with the "weaning reaction," a time during which the microbiota imprints durable oral tolerance. Recent work has shown that children with FA manifest an early onset dysbiosis with the loss of Clostridiales species, which promotes the differentiation of ROR-γt+ regulatory T cells to suppress FA. This process can be reversed in pre-clinical mouse models by targeted bacteriotherapy. Here, we review the dominant tolerance mechanisms enforced by the microbiota to suppress FA and discuss therapeutic intervention strategies that act to recapitulate the early life window of opportunity in stemming the FA epidemic.
Asunto(s)
Dieta , Disbiosis/microbiología , Hipersensibilidad a los Alimentos/inmunología , Microbioma Gastrointestinal/fisiología , Animales , Clostridiales/aislamiento & purificación , Desensibilización Inmunológica/métodos , Humanos , Tolerancia Inmunológica/inmunología , Inmunoglobulina E/inmunología , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunologíaRESUMEN
The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1-3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.
Asunto(s)
Alérgenos , Reacción de Prevención , Hipersensibilidad , Mastocitos , Animales , Ratones , Alérgenos/inmunología , Reacción de Prevención/fisiología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Estómago/inmunología , Vagotomía , Inmunidad Innata/inmunología , Inmunidad Mucosa/inmunología , Células Th2/inmunología , Citocinas/inmunología , Leucotrienos/biosíntesis , Leucotrienos/inmunología , Intestino Delgado/inmunologíaRESUMEN
In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour1,2. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Here, using mouse models of food allergy, we show that allergic sensitization drives antigen-specific avoidance behaviour. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus and central amygdala. Allergen avoidance requires immunoglobulin E (IgE) antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote avoidance requires cysteinyl leukotrienes and growth and differentiation factor 15. Finally, a comparison of C57BL/6 and BALB/c mouse strains revealed a strong effect of the genetic background on the avoidance behaviour. These findings thus point to antigen-specific behavioural modifications that probably evolved to promote niche selection to avoid unfavourable environments.
Asunto(s)
Alérgenos , Reacción de Prevención , Hipersensibilidad a los Alimentos , Animales , Ratones , Alérgenos/inmunología , Reacción de Prevención/fisiología , Núcleo Amigdalino Central/fisiología , Modelos Animales de Enfermedad , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/inmunología , Inmunoglobulina E/inmunología , Intestinos/inmunología , Mastocitos/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Núcleos Parabraquiales/fisiología , Núcleo Solitario/fisiologíaRESUMEN
Mast cells are evolutionarily ancient sentinel cells. Like basophils, mast cells express the high-affinity receptor for immunoglobulin E (IgE) and have been linked to host defense and diverse immune-system-mediated diseases. To better characterize the function of these cells, we assessed the transcriptional profiles of mast cells isolated from peripheral connective tissues and basophils isolated from spleen and blood. We found that mast cells were transcriptionally distinct, clustering independently from all other profiled cells, and that mast cells demonstrated considerably greater heterogeneity across tissues than previously appreciated. We observed minimal homology between mast cells and basophils, which shared more overlap with other circulating granulocytes than with mast cells. The derivation of mast-cell and basophil transcriptional signatures underscores their differential capacities to detect environmental signals and influence the inflammatory milieu.
Asunto(s)
Basófilos/fisiología , Células Sanguíneas/fisiología , Células del Tejido Conectivo/fisiología , Mastocitos/fisiología , Bazo/citología , Animales , Separación Celular , Células Cultivadas , Citometría de Flujo , Perfilación de la Expresión Génica , Inmunoglobulina E/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Matrices TisularesRESUMEN
Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcÉRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.
Asunto(s)
Autoanticuerpos/inmunología , Autoinmunidad , Inmunoglobulina E/inmunología , Interferones/metabolismo , Anticuerpos Antinucleares/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Masculino , Fagocitosis/inmunología , Fagosomas/metabolismo , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptor Toll-Like 9/metabolismoRESUMEN
Aberrant production of IgE antibodies can lead to allergic diseases. Normally, IgE(+) B cells rarely differentiate into memory B cells (Bmem) or long-lived plasma cells (LLPCs), as they only transiently participate in the germinal center (GC), but the mechanism behind this remains elusive. We found that membrane IgE (mIgE) autonomously triggered rapid plasma-cell differentiation and apoptosis independently of antigen or cellular context, predominantly through the mutually independent CD19-PI3K-Akt-IRF4 and BLNK-Jnk/p38 pathways, respectively, and we identified the ectodomains of mIgE as being responsible. Accordingly, deregulated GC IgE(+) B cell proliferation and prolonged IgE production with exaggerated anaphylaxis were observed in CD19- and BLNK-deficient mice. Our findings reveal an autonomous mIgE signaling mechanism that normally prevents IgE(+) Bmem and LLPC formation, providing insights into the molecular pathogenesis of allergic diseases.